Irisin is a hormone secreted by skeletal muscle, able to improve metabolic homeostasis and promote energy expenditure. We have previously demonstrated that irisin protects human and rodent β-cells and pancreatic islets from lipotoxicity-induced apoptosis, increases insulin biosynthesis and glucose-stimulated insulin secretion (GSIS), and promotes β-cell proliferation, both in vitro and in vivo in mice. Irisin may also restore the defects that are characteristic of islets from T2D patients. Although it has been demonstrated that irisin mediates its effects on bone and fat via αV integrin receptors, the presence of an irisin receptor in β-cells has not been reported. In INS-1E cells, we found that irisin activates its intracellular signalling and enhances GSIS in the presence of a specific αV integrin knockdown or a chemical inhibitor of cellular integrins (RGDS), thus excluding the involvement of integrin receptors in irisin effects. Through a pull-down assay/mass spectrometry approach, we identified 102 irisin interactors in human pancreatic islets, mostly belonging to intracellular compartments (i.e., vesicles and membrane rafts), and not including canonical membrane receptors. We therefore hypothesized that irisin could be endocytosed in pancreatic β-cells and confirmed this by immunoblotting and immunofluorescence techniques. In addition, nystatin, an inhibitor of lipid-raft dependent endocytosis, reduced irisin entry into β-cells. These results suggest for the first time that irisin effects on pancreatic β-cells are independent of engaging the αV integrin receptor and may instead depend on its endocytosis. These results are important beyond irisin, as they propose a potential new mechanism of action for peptide hormones. In addition, we highlight the possibility that the same hormone, i.e. irisin, may signal through different receptors in different target tissues.


N.Marrano: None. A.Borrelli: None. G.Biondi: None. M.Rella: None. A.Cignarelli: Speaker's Bureau; Eli Lilly and Company, Novo Nordisk, Sanofi. S.Perrini: None. L.Laviola: Advisory Panel; A. Menarini Diagnostics, Boehringer Ingelheim Inc., Eli Lilly and Company, Novo Nordisk, Roche Diabetes Care, Sanofi, Other Relationship; Medtronic, Speaker's Bureau; Abbott, Terumo Corporation. F.Giorgino: Advisory Panel; Boehringer-Ingelheim, Amarin Corporation, Medtronic, Roche Diabetes Care, Sanofi, Bayer Inc., Novo Nordisk, Consultant; Novo Nordisk, Lilly, Research Support; Lilly, Roche Diabetes Care, AlfaSigma, Speaker's Bureau; Abbott, Boehringer-Ingelheim, Lilly, Sanofi, Medscape. A.Natalicchio: Other Relationship; AstraZeneca, Novo Nordisk, Sanofi, Boehringer-Ingelheim, Lilly.

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